Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) infects nearly 1 in 3 people in the world with over 11 million people co-infected with HIV and Mtb. TB remains the major cause of death in HIV patients worldwide. Most morbidity associated with TB in HIV patients is due to uncontrolled infection as a result of immunodeficiency. As effective anti-retroviral therapy has become available, however, new syndromes have been recognized, which are thought to result from an inflammatory response during immune reconstitution. These syndromes, termed Immune Reconstitution Inflammatory Syndrome (IRIS), develop in about 30% of active TB patients beginning effective antiretroviral therapy. The immunopathogenesis of IRIS is poorly understood, but seems to involve an overly exuberant immune/inflammatory response to microbial antigens. A subset of CD4 T cells, termed T regulatory (Treg) cells, has been recognized that are involved in modulating T cell and inflammatory responses. Tregs were initially recognized by their expression of CD4 and CD25 (the IL2 receptor alpha chain), markers also shared with activated T cells. More recently, Tregs were found to uniquely express the transcription factor Foxp3. In prior studies, we have demonstrated a complex relationship between Tregs and HIV. There was a decrease in total number of Foxp3+ Tregs in parallel to the decrease in total CD4+ cell numbers. However, the proportion of CD4 cells positive for Foxp3 was variable in advanced disease. Furthermore, IRIS develops mainly in those with low proportions of Foxp3+ cells. The broad hypothesis for this proposal is that Treg number and function are depressed in HIV-Mtb co-infected patients and that Treg defects predispose co-infected patients to chronic immune activation and IRIS, The current proposal will determine the role of Treg cells in the immunopathogenesis of IRIS by prospectively studying a cohort of HIV-TB co-infected patients beginning antiretroviral therapy. The specific aims are to test the hypothesis that HIV-TB patients who develop IRIS have a decrease of regulatory T cell proportions prior to starting antiretroviral therapy (aim1), to compare the immunogenetics of AIDS patients with tuberculosis who do and do not develop IRIS (aim 2), to test the hypothesis that IRIS in TB patients is associated with an exaggerated antigen-driven response to TB peptides (aim 3), and to TB-specific Treg function in patients with or without IRIS reconstitute a TB peptide-specific regulatory cell response (aim 4). To accomplish these goals, we have assembled a team of accomplished investigators from Texas and experienced clinician-investigators from Lima, Peru, with a large population of HIV-TB co-infected patients now beginning antiretroviral therapy. These studies should elucidate abnormalities in immunoregulation that predispose to IRIS, a problem emerging and provide a better scientific basis for optimizing antiretroviral therapy in TB endemic areas. PUBLIC HEALTH RELEVANCE Immune reconstitution inflammatory syndrome significantly complicated treatment of AIDS in areas where tuberculosis is common. This study will identify genetic and immune risk factors for this syndrome. The information will be important for improving treatment for the large number of people with both infections in developing countries, as well as in the United States.